Circulation
AHA SCIENTIFIC STATEMENT Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV A Scientific Statement From the American Heart Association
ABSTRACT: As early and effective antiretroviral therapy has become more Matthew J. Feinstein, widespread, HIV has transitioned from a progressive, fatal disease to a MD, MSc, FAHA, Chair chronic, manageable disease marked by elevated risk of chronic comorbid Priscilla Y. Hsue, MD, Vice diseases, including cardiovascular diseases (CVDs). Rates of myocardial Chair infarction, heart failure, stroke, and other CVD manifestations, including Laura A. Benjamin, PhD pulmonary hypertension and sudden cardiac death, are significantly Gerald S. Bloomfield, MD, higher for people living with HIV than for uninfected control subjects, MPH, FAHA even in the setting of HIV viral suppression with effective antiretroviral Judith S. Currier, MD therapy. These elevated risks generally persist after demographic and Matthew S. Freiberg, MD, MSc clinical risk factors are accounted for and may be partly attributed to Steven K. Grinspoon, MD chronic inflammation and immune dysregulation. Data on long-term Jules Levin, MS Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 CVD outcomes in HIV are limited by the relatively recent epidemiological Chris T. Longenecker, MD, transition of HIV to a chronic disease. Therefore, our understanding FAHA of CVD pathogenesis, prevention, and treatment in HIV relies on large Wendy S. Post, MD, MS observational studies, randomized controlled trials of HIV therapies that On behalf of the American are underpowered to detect CVD end points, and small interventional Heart Association studies examining surrogate CVD end points. The purpose of this Prevention Science document is to provide a thorough review of the existing evidence Committee of the Council on HIV-associated CVD, in particular atherosclerotic CVD (including on Epidemiology and myocardial infarction and stroke) and heart failure, as well as pragmatic Prevention and Council recommendations on how to approach CVD prevention and treatment on Cardiovascular and Stroke Nursing; Council in HIV in the absence of large-scale randomized controlled trial data. This on Clinical Cardiology; statement is intended for clinicians caring for people with HIV, individuals and Stroke Council living with HIV, and clinical and translational researchers interested in HIV- associated CVD.
Key Words: AHA Scientific Statements ◼ cardiovascular diseases ◼ HIV ◼ preventive medicine
© 2019 American Heart Association, Inc.
https://www.ahajournals.org/journal/circ
Circulation. 2019;139:00–00. DOI: 10.1161/CIR.0000000000000695 TBD TBD, 2019 e1 Feinstein et al Cardiovascular Disease in People With HIV
ith contemporary antiretroviral therapy (ART), risks.5,25–27 Several studies have found that lower CD4 people living with HIV (PLWH) are living lon- count is associated with higher MI risks5,25–27; similarly, ger1 and experiencing a rising burden of car- a lower CD4/CD8 ratio is associated with more coro- W 2,3 28 diovascular diseases (CVDs). Relative risks of various nary atherosclerosis. Moreover, PLWH who achieve CVD manifestations are generally 1.5- to 2-fold greater sustained HIV viral suppression5 or have few, if any, for PLWH compared with uninfected individuals.4 Al- cardiovascular risk factors23 have higher MI risks than though the relative risk has decreased with effective people without HIV infection. This excess MI risk may AND GUIDELINES ART, there is a large and rising absolute burden of CVD be greater among women living with HIV/AIDS.24,29 CLINICAL STATEMENTS STATEMENTS CLINICAL among PLWH (conceptual model in Figure 1).2–4 In a PLWH also have significantly elevated risks for stroke. In meta-analysis of 793 635 individuals with a total of 3.5 HIV-endemic populations in Sub-Saharan Africa, HIV is million person-years of follow-up, the global burden of the leading risk factor for stroke in young cohorts, with HIV-associated CVD tripled over the past 2 decades and a population-attributable fraction of almost 50%.30 accounted for 2.6 million disability-adjusted life-years Women with HIV may be at particularly elevated risk per year, with the greatest impact in Sub-Saharan Af- compared with uninfected women.31 Both immunosup- rica and the Asia-Pacific regions (Figure 2).4 PLWH have pression and HIV viremia appear to be risk factors: Both an excess risk of myocardial infarction (MI),5,6 ischemic lower CD4 count and higher levels of HIV viremia are stroke,7,8 heart failure (HF),9,10 pulmonary hyperten- associated with greater stroke risk.7,30,32–34 Coinfection sion,11,12 and venous thrombosis.13,14 Underlying mech- with HIV and hepatitis C (versus HIV infection alone) anisms likely include an interplay among traditional risk may increase stroke risk further.35 factors, HIV-specific factors (eg, chronic immune acti- vation/inflammation),15,16 ART-related dyslipidemia and other metabolic comorbidities,17,18 behavioral factors HIV-ASSOCIATED HF 5,19 (eg, smoking), and disparities in access to or receipt Given the excess risk of coronary heart disease, it is not of care.20–22 surprising that PLWH also have elevated HF risks, with current estimates ranging from a 1.5- to 2-fold greater HIV-ASSOCIATED ATHEROSCLEROTIC risk for HF among PLWH compared with uninfected individuals after adjustment for relevant confound- 9,10,36,37 Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 CVD: MI AND STROKE ers. However, this excess risk is not entirely attrib- Over the past decade, a variety of studies from around utable to MI; after adjustment for prior MI, PLWH still the world have reported an excess risk of MI among have a >1.5-fold higher hazard for HF than uninfected PLWH compared with uninfected people. The risk rang- individuals.10 This risk extends to both HF with preserved es from a 50% relative risk increase to a doubling of ejection fraction (HFpEF) and HF with reduced ejection risk.5,23–25 Regardless of study, HIV-related viremia and fraction (EF). Similar to MI risks, unsuppressed HIV viral immune dysfunction are associated with higher MI load and lower CD4 count are associated with higher
Figure 1. Conceptual model of the changing epidemiology of myocardial infarction (MI) and heart failure (HF) risk in HIV. ART indicates antiretroviral therapy; and CVD, cardiovascular disease.
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Figure 2. Global burden of atherosclerotic cardiovascular disease in people living with HIV. A, Population-attributable fraction by country and (B) disability-adjusted life-years per 100 000 people by country. Reprinted from Shah et al.4 Copyright © 2018, American Heart Association, Inc.
HF risks for PLWH.10,38 The epidemiology and charac- have reported that PLWH have an excess risk of periph- teristics of HF in HIV are discussed in greater detail in eral artery disease compared with uninfected individu- the HF Pathogenesis and Presentation in HIV section als.42,43 HIV-related pulmonary arterial hypertension has of this document. been well described since the 1990s and is considered to be in group 1 of the World Health Organization clas- sification of pulmonary hypertension.44–49 The preva- OTHER MANIFESTATIONS OF CVD lence of HIV-associated pulmonary arterial hypertension In contrast to the evidence linking HIV infection to MI, is considerably higher than pulmonary arterial hyper- HF, and stroke, there are fewer studies of atrial fibril- tension in the general population,50 and ART has not lation, sudden cardiac death, and peripheral artery changed this epidemiology.51 Elevated pulmonary ar- disease. However, 1 study reported that PLWH have a tery systolic pressure has also been reported in HIV.11,52 4-fold greater rate of sudden cardiac death compared As a result of limited data, treatment goals are similar with expected rates in the general population.39 Low to those of other pulmonary arterial hypertension sub- CD4 counts (<200 cells/mm3) are associated with el- groups.53 Finally, given the confluence of sleep disor- evated incidence40 and prevalence41 of atrial fibrillation ders, particularly obstructive sleep apnea, with CVD,54 among PLWH, but it is unclear whether PLWH without it is also worth noting that HIV is associated with sleep detectable HIV viremia or immune compromise have el- impairment in general55–57 and that obstructive sleep evated atrial fibrillation risks. Similarly, several studies apnea may be underdiagnosed among PLWH.58,59
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PATHOPHYSIOLOGY AND Although treatment with ART reduces levels of circu- PRESENTATION OF ATHEROSCLEROTIC lating inflammation markers, many markers of inflam- mation remain elevated with viral suppression in PLWH CVD AND HF IN HIV relative to uninfected individuals.79 Furthermore, several After 2 decades of progress in studying the elevated studies have included PLWH who are able to maintain risks for CVD among PLWH, the underlying mechanisms an undetectable HIV RNA level despite not being on and biology of this process still remain incompletely de- ART (elite controllers) and demonstrated heightened AND GUIDELINES fined. Furthermore, delineating risk that is attributable levels of subclinical vascular disease79,80 and clinical CLINICAL STATEMENTS STATEMENTS CLINICAL to HIV disease itself versus ART versus traditional risk events in this population relative to uninfected control factors is challenging because many of these factors subjects.81 Inflammation is also elevated with hepatitis are interrelated. The pathophysiology of HIV-associated C coinfection and, if left untreated, may contribute to CVD is multifactorial and includes the interplay among the development of atherosclerosis.82 Lymph node ac- traditional risk factors, exposure to ART and virological tivity is even more pronounced in individuals with treat- suppression, and chronic inflammation/immune activa- ed HIV compared with uninfected people and is closely tion that persists in the setting of treated HIV in the linked to HIV disease characteristics, suggesting that face of an aging HIV population. An older person with a distinct patterns of immune activation exist73 and that history of HIV for decades likely has a distinct risk profile interventions to reduce HIV reservoirs may not predict- for CVD compared with a newly diagnosed individual ably affect arterial inflammation. Despite the fact that who was started on newer ART immediately. PLWH the SMART study (Strategies for Management of Anti- have high rates of traditional risk factors, including dys- retroviral Therapy) demonstrated the key role of chronic 83 lipidemia, metabolic disease, smoking, hypertension, inflammation in HIV-associated CVD >10 years ago, and substance use, as described in the sections below. effective interventions designed to lower inflammation Aside from traditional risk factors, HIV-specific issues in treated HIV have been elusive. are implicated in CVD and include ART, chronic inflam- Large studies with hard clinical end points of com- mation, and immune activation in the setting of treated mon cardioprotective therapies such as statins and as- and suppressed HIV disease. Imaging techniques have pirin have not been completed in HIV. Small therapeutic provided valuable insight into CVD onset and progres- studies of statins and aspirin targeting inflammation/ coagulation (eg, hsCRP [high-sensitivity C-reactive pro- Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 sion in HIV. tein], IL-6, and D-dimer) among PLWH or HIV-specific therapies have not reported consistent results.84–86 Al- Atherosclerosis Pathophysiology in terations in gut permeability and subsequent microbial HIV: Chronic Inflammation and Immune translocation result in downstream chronic inflamma- Activation tion and immune activation. Therapeutic interventions that have targeted the gut, including rifaximin,87 Numerous studies have demonstrated that chronic in- sevelamer,88 and mesalamine,89 have not consistently flammation and immune activation are abnormal in reduced circulating inflammatory markers or markers of the setting of treated HIV infection60–64 and, in turn, immune activation. In the general population, a mono- are strongly predictive of mortality, non-AIDS events,65 clonal antibody to IL-1β had no impact on low-density and CVD.66–69 Higher levels of several inflammatory lipoprotein (LDL) cholesterol (LDL-C) but significantly markers, including IL (interleukin)-6 and soluble tumor reduced inflammatory markers cardiovascular events90 necrosis factor receptors α-1 and α-2, have been as- and, in an analysis of nonprimary end points, also re- sociated with coronary atherosclerosis in HIV.70,71 Ar- duced lung cancer mortality.91 Individuals whose hsCRP terial inflammation as assessed by fluorodeoxyglucose was reduced by <2 mg/L had a 25% reduction in major positron emission tomography/computed tomography CVD events, a 31% reduction in CVD mortality, and a (CT) is higher in the setting of HIV72–74 and relates to 31% reduction in all-cause mortality.92 In a small study circulating inflammatory markers. Likewise, elevated of treated PLWH, IL-1β inhibition significantly reduced levels of monocyte activation markers, including sol- IL-6, hsCRP, and arterial and bone marrow inflamma- uble CD163 and soluble CD14, are associated with tion.93 In contrast, among ART-treated PLWH, low-dose coronary atherosclerosis and carotid plaque progres- methotrexate did not affect inflammatory markers but sion.75–77 However, it is worth noting that a recent reduced levels of CD8+ T cells and T-cell activation.94 systematic review did not identify a clear association between inflammatory markers and surrogate CVD Atherosclerosis Pathophysiology in HIV: outcomes in HIV.78 Whether this is the result of insuf- ficient follow-up data in the studies reviewed (the vast Metabolic Contributors majority of which were cross-sectional) or a lack of a HIV infection is associated with metabolic complica- strong association is not clear. tions, including dyslipidemia, insulin resistance, and
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body composition changes, which can contribute to ated with increased coronary plaque, including both CLINICAL STATEMENTS
CVD. Initially, dyslipidemia in HIV was characterized by noncalcified and calcified plaque.114,115 AND GUIDELINES increased triglyceride levels, thought to be related to immunodeficiency in the pre-ART era.95 Later, specific ART medications, including several protease inhibitors Atherosclerosis Pathophysiology (PIs) and efavirenz, a non–nucleoside reverse transcrip- in HIV: ARTs tase inhibitor (NRTI), were associated with dyslipidemia ART is a critical component of ASCVD prevention be- (particularly elevated triglyceride levels).96–99 However, cause treatment interruption and uncontrolled HIV vi- current first-line ART regimens have minimal lipid ef- remia are associated with elevated risk of MI.5,83 There fects.100 Over time, additional research has suggested were too few ASCVD events in the START trial (Strate- that inflammation and other factors may contribute to gic Timing of AntiRetroviral Treatment) to definitively an atherogenic dyslipidemia, with low high-density li- answer whether immediate ART for all PLWH reduces poprotein cholesterol and increased oxidized LDL-C in ASCVD risk,116 and changes in ASCVD risk factors levels association with increased innate immune activation.101 were not clearly positive or negative.117 Thus, the im- In contrast, overall levels of LDL-C are often not ele- pact of early ART on ASCVD is uncertain. vated in PLWH; levels can be low with initial infection Certain antiretroviral drugs and drug classes have and related inflammation and then return to normal been associated with elevated risk of ASCVD events, levels with improved health on ART.102 Dyslipidemia in most notably among people with higher levels of tra- HIV may contribute to elevated atherosclerotic CVD ditional risk factors. PIs were first associated with MI in (ASCVD) risk and has been shown to contribute inde- the landmark D:A:D study (Data Collection on Adverse pendently to ASCVD among PLWH.103 The specific con- Events of Anti-HIV Drugs),118 in which each year of cu- tributions of dyslipidemia to ASCVD events in HIV are mulative PI use was associated with a 10% greater risk an important area for future investigation. of MI, even after adjustment for cholesterol changes Insulin resistance and diabetes mellitus are also seen caused by PIs. Analyses from the D:A:D cohort of ata- with increasing frequency in HIV.104 Prevalence estimates zanavir and darunavir, 2 current-generation PIs in wide- range up to 26% and 47% in Sub-Saharan Africa for spread clinical use, suggest that ritonavir-boosted or diabetes mellitus and prediabetes mellitus, respective- unboosted atazanavir is not associated with increased ly. 99 Mechanisms may relate to effects of specific ART risk, whereas cumulative exposure to ritonavir-boosted Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 on glucose translocation,105 inflammation, and lipodys- darunavir is associated with progressively increasing risk trophy. Diabetes mellitus has been linked to ASCVD in for CVD.119,120 Rates of carotid intima-media thickness HIV such that PLWH with diabetes mellitus have a 2.4- (IMT) progression were also noted to be slower with fold increased risk of coronary heart disease events.106 boosted atazanavir compared with darunavir and rito- Body composition changes are common in HIV. Pa- navir in a randomized trial, with some of the proposed tients presenting in the initial era of ART often dem- benefit thought to be the result of the bilirubin-increas- onstrated relative loss of subcutaneous fat and gain in ing effect of atazanavir.121 In contrast, the association of abdominal visceral fat.107 The changes in fat distribution higher bilirubin with lower mortality in a Veterans Af- were often heterogeneous and frequently were associ- fairs study was not mediated by atazanavir use,122 and ated with insulin resistance and deposition of ectopic another mechanistic clinical trial showed mixed effects adipose in the liver and muscle. Multiple factors con- of atazanavir on surrogate CVD risk markers (reduced tributed to these changes, including effects of ART. Use oxidative stress but increased von Willebrand factor and of specific thymidine NRTIs is associated with subcuta- no effect on endothelial function).123 It appears that the neous fat loss and deposition of ectopic adipose tissue association of PIs with ASCVD events is a class effect, in the liver and muscle, as well as arterial inflamma- with atazanavir being the exception. tion.108 Early PI therapy was associated with increased NRTIs have also evolved over time, with newer gen- abdominal fat gain. erations of these drugs having fewer metabolic side In the modern ART era, this phenotype has changed, effects and presumed less mitochondrial toxicity124; and recent work has focused on dysfunctional subcuta- however, abacavir is a widely used NRTI that has been neous fat, related in part to the effect of HIV on peroxi- associated with increased risk of MI in observational some proliferator-activated receptor-γ and Dicer, as well studies. The association of current or recent abacavir as other mechanisms.109,110 With increasingly effective use with MI was first described in the D:A:D cohort in ART, gains in both subcutaneous and visceral fat are 2008,125 with subsequent D:A:D analyses demonstrat- often seen with the initiation of ART, regardless of regi- ing that the hazard ratio did not change substantially men,111 and rates of generalized obesity are increasing although abacavir use among individuals at high CVD among PLWH.112 Changes in body composition, includ- risk decreased over time.126 Similar associations of ing excess visceral adipose tissue, have been linked to abacavir with CVD risk have been shown in the Kai- overall mortality.113 These changes have been associ- ser Permanente California health system127 and NA-
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ACCORD (North American AIDS Cohort Collaboration for PLWH compared with 24% for general population on Research and Design).128 Possible mechanisms of risk control subjects.144 These data underscore the critical include endothelial dysfunction,129 vascular inflamma- public health importance of including smoking cessa- tion, and platelet hyperreactivity.130 Despite guideline tion as a cornerstone of any efforts related to CVD pre- recommendations to avoid abacavir or to use it with vention in HIV. caution in patients at high CVD risk,131 the issue re- Heavy alcohol use, although not generally considered mains controversial because of meta-analyses (US Food a traditional atherosclerotic risk factor, may contribute AND GUIDELINES and Drug Administration and industry funded) that disproportionately to CVD among PLWH.19 In addition CLINICAL STATEMENTS STATEMENTS CLINICAL demonstrated no significant effect of abacavir on MI to (and often in conjunction with) substance use dis- among generally low-risk individuals in shorter-duration orders, mood and anxiety disorders are quite common clinical trials.132,133 among PLWH146–148 and may contribute to elevated The population-level impact of ART toxicities on AS- CVD risk (including MI149 and HF36). PLWH also have low CVD risk among PLWH may be relatively low134 and may levels of physical and cardiorespiratory fitness, which be further attenuated by the use of antiplatelet agents are associated with vascular dysfunction, inflammation, and statins among high-risk individuals.135 The decision and risk for CVD, as well as all-cause mortality, in pa- of what ART to start and whether to switch because of tients with HIV (and in the general population).150–153 comorbidities or side effects is complex and depends on many factors, including cardiovascular risk assessment, HLA-B*57:01 testing (for hypersensitivity to abacavir), Atherosclerosis Pathophysiology in HIV: HIV resistance testing, medication compliance, preg- Insights From Imaging nancy/child-bearing age, and other comorbidities such PLWH have more subclinical atherosclerosis relative to as bone and renal disease. those who are uninfected as measured with a variety of imaging modalities. Carotid ultrasound studies have Atherosclerosis Pathophysiology demonstrated that PLWH have more carotid plaque in HIV: Hypertension, Smoking, and higher IMT compared with uninfected individuals in cross-sectional and longitudinal studies.66,154,155 The and Other Factors pattern of atherosclerosis progression in the carotid ar- Other traditional risk factors, including hypertension tery has been demonstrated to be particularly marked Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 and cigarette smoking, play an important role in the in the bifurcation region.66 Whereas some studies of ca- pathogenesis of ASCVD in PLWH. A meta-analysis of rotid IMT have not found an association with HIV,156 the 63 554 participants from studies published from 2011 majority of studies demonstrate significantly higher IMT to 2016 estimated hypertension prevalence to be 35% for PLWH than uninfected control subjects.157 for PLWH on ART and 13% for ART-naïve PLWH.136 Al- Imaging with noncontrast CT allows measurement though untreated HIV is typically associated with lower of coronary artery calcium (CAC), which has been blood pressure, resulting perhaps from uncontrolled in- shown to progress more rapidly in PLWH compared flammation and periseptic states of vascular permeabil- with HIV-negative individuals.158 Coronary CT angiog- ity,136–138 studies are inconsistent on whether individuals raphy provides visualization of both calcified and non- with treated HIV have a higher prevalence of hyperten- calcified components of atherosclerotic plaque. HIV sion compared with uninfected individuals.139–141 Mech- is associated with a greater prevalence and extent of anisms of hypertension in PLWH may include chronic noncalcified plaque159–161 and with coronary artery re- inflammation and activation of the renin-angiotensin- modeling.162,163 Both of these atherosclerotic features aldosterone system.141,142 Overt hypertension, prehy- predispose to plaque rupture and may represent a phe- pertension, and borderline hypertension (systolic blood notype of elevated risk associated with HIV infection. pressure, 120–140 mm Hg) were associated with great- Treatment with statin therapy reduced noncalcified er risk for acute MI in VACS (Veterans Aging Cohort plaque volume and high-risk plaque features relative Study), but there was no evidence that this association to placebo in a small pilot study.84 The effects of statin was stronger among PLWH compared with uninfected therapy on coronary atherosclerosis in PLWH are being people.140 comprehensively evaluated in a substudy of the ongo- On a population-level scale, smoking may be the ing REPRIEVE trial (Randomized Trial to Prevent Vascular most important modifiable CVD risk factor among Events in HIV; URL: ClinicalTrials.gov. Unique identifier: PLWH. Smoking is highly prevalent among PLWH (42% NCT02344290). were current smokers and 20% were former smok- Arterial inflammation can be measured with18 F-fluo- ers in a nationally representative US sample143) and is rodeoxyglucose positron emission tomography imaging strongly associated with coronary artery plaque and of the aorta relative to venous background. PLWH have MI.144,145 In 1 study, the population-attributable frac- greater aortic arterial inflammation than uninfected in- tion for MI associated with ever smoking was 72% dividuals with similar cardiovascular risk factors.72 Arte-
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rial inflammation is associated with soluble CD163, a HF Pathogenesis and Presentation CLINICAL STATEMENTS marker of monocyte activation, with visceral fat, and in HIV AND GUIDELINES with high-risk coronary atherosclerotic plaque.164 Arte- rial inflammation is a process that appears to be inde- Myocardial dysfunction and HF have been known pendent of HIV disease activity as measured by inflam- complications of HIV since the first reports of AIDS 176–178 mation seen in the lymph nodes.73 cardiomyopathy in the 1980s. Cases of AIDS car- diomyopathy in the pre-ART era were common and marked by progressive viremia and immune dysfunc-
Stroke Pathophysiology and Presentation tion, opportunistic infection, and global ventricular in HIV dysfunction, with myocarditis commonly seen on pa- 178–180 The phenotypes of extracranial (eg, carotid and ver- thology. As HIV has evolved from a fatal disease tebral) and intracranial (eg, middle cerebral and per- marked by severe immune compromise and viremia to forator) arteries are distinct and differ in their degree a chronic, manageable disease marked by inflamma- of media and adventitia thickness and presence or ab- tion and variable immune dysfunction, the pathophys- sence of dura mater. The additional barrier from the iology and characteristics of myocardial dysfunction blood-brain interface, which is relevant to intracranial and HF in HIV have likewise evolved. Diastolic dys- arteries, prevents systemic infection and freely circu- function and HF associated with coronary artery dis- 181 lating antibodies in the brain. However, HIV infection ease have become more common among PLWH. A manipulates this barrier and enters an immune-naïve seminal contemporary study from VACS demonstrated brain early during primary infection.165 These character- that PLWH followed up since 2003 had significantly istics influence how extracranial and intracranial arter- higher risks than uninfected individuals for HF over- 10 ies respond to vascular risk factors and inflammation. all. After adjustment for possible confounders, PLWH Common pathways of atherosclerosis and CVD events had significantly higher risks for each HF phenotype relate more closely to extracranial (eg, proximal carotid analyzed: HF with reduced EF, HFpEF, and borderline arteries and aorta) than intracranial arterial causes of HFpEF. Among PLWH, the most common incident HF ischemic stroke.166 cases were HF with reduced EF (40%), followed by The body of evidence on the pathogenesis of HIV HFpEF (30%), then borderline HFpEF (15%), and then infection and CVD pertains largely to extracranial dis- HF with unknown EF (15%). As expected, worse HIV Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 ease.143,167,168 However, more than one-third of ischemic viremia and related immune dysfunction were associ- stroke in HIV is the result of intracranial disease.169,170 ated with the highest risks for HF in this study and an- Advanced HIV infection is associated with secondary other that used physician-adjudicated HF end points.38 causes of ischemic stroke such as opportunistic infec- Nevertheless, PLWH with viral control (HIV viral RNA tion (eg, varicella zoster) and coagulopathy.169,170 Once <500 copies/mL) and minimal immune compromise an individual is on ART, HIV-associated vasculopathy, (CD4 ≥500 cells/mm3) were still significantly more which encompasses several subtypes (eg, atherosclero- likely than uninfected individuals to have HF.10 The sis, HIV-associated vasculitis, nonatherosclerotic vascu- greater HF risks among PLWH remained after restric- lopathy, and small vessel disease), becomes more preva- tion to nonhypertensive people without documented lent.169–171 Knowledge about intracranial HIV-associated alcohol, tobacco, or cocaine abuse and after adjust- vasculopathy is sparse. However, emerging data sug- ment for MI. This suggests that the higher risk for HF gest that vessel wall remodeling occurs through neu- in HIV is not solely attributable to substance abuse or roinflammation and that this may be independent of MI, although residual confounding from drug use is atherosclerosis.172,173 Furthermore, as the immune sys- possible given underreporting by patients. Studies in tem recovers, thinning and erosion of intracranial ar- different cohorts and settings have likewise demon- teries ensue.174 The latter is in keeping with the first strated elevated rates of HF in PLWH.29,182 In regions of 6 months of ART in immunosuppressed patient be- the world where HIV disease control rates are low, the ing associated with a high risk of stroke.30 Although pattern of HIV-associated HF still resembles the pre- neuroinflammation appears to be an important factor, ART epidemiology.183 The prognosis of HF in HIV also it remains unclear whether this occurs in conjunction may be worse, with a recent small study finding signif- with or independently of atherosclerosis and warrants icantly higher rates of HF hospitalization and mortality further investigation. Nevertheless, as pharmacologi- among women with HIV compared with uninfected cal strategies evolve for CVD prevention in HIV (rang- women.184 ing from statins with demonstrated stroke prevention In light of the still-evolving epidemiology, data inves- benefit175 to newer anti-inflammatory drugs), consider- tigating mechanisms and phenotypes of HIV-associated ation for those that cross the blood-brain barrier will be HF in the modern ART era are limited. However, sev- critical in addressing the burden of intracranial arterial eral cross-sectional studies have indicated that subclini- disease in the future. cal myocardial disease is particularly prevalent among
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AND GUIDELINES CLINICAL STATEMENTS STATEMENTS CLINICAL
Figure 3. Proposed mechanisms of myocardial dysfunction and heart failure in HIV. ART indicates antiretroviral therapy.
PLWH. On cardiac magnetic resonance imaging and subsequent cardiac magnetic resonance imaging sug- CT, PLWH have more myocardial fibrosis and steatosis gested.192 Furthermore, microvascular dysfunction is a than uninfected control subjects; these subclinical ab- contributor to diastolic dysfunction and HFpEF193 and Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 normalities are closely associated with myocardial in- may play a role given the association of HIV-related jury and mechanical dysfunction among PLWH.185–187 inflammation and immune dysfunction with micro- PLWH with a history of advanced immune suppression vascular disease.194 are at higher risk of left ventricular hypertrophy and Nonvascular mechanisms are also implicated in diastolic dysfunction than PLWH with preserved im- HIV-associated myocardial dysfunction and HF. Sub- mune function.188 Likewise, PLWH have a substantially stance use is a common cause of cardiomyopathy higher prevalence of diastolic dysfunction and higher and HF in general and is common in HIV (particularly left ventricular mass index than uninfected people on alcohol, methamphetamine, and cocaine). However, echocardiography, independently of demographics and this is unlikely to be the primary driver of HF in HIV, cardiovascular risk factors.189 particularly in light of the aforementioned VACS anal- The pathophysiology underlying subclinical myo- ysis demonstrating greater HF risks in HIV after the cardial dysfunction and overt HF in HIV is less clearly analyses were restricted to people without substance defined. A substantial portion of PLWH in low- and use.10 Cardiac arrhythmias contribute to myocardial middle-income countries (and some in high-income dysfunction and may be particularly common in HIV. countries) are not on ART, have uncontrolled HIV, and PLWH appear to have a several-fold greater risk of remain at risk for severe myocardial inflammation, fi- sudden death than uninfected people, although the brosis, and systolic dysfunction characteristic of AIDS extent to which malignant arrhythmias drive these cardiomyopathy.178,179,190 For PLWH on ART with viral sudden deaths is not known.39 Although worse HIV control, several mechanisms may predispose them disease severity is associated with atrial arrhythmias to myocardial dysfunction and HF (Figure 3). Given among PLWH,40,41 atrial arrhythmias were no more the predilection of PLWH for atherosclerosis, throm- common among PLWH than in uninfected individuals bosis, and MI, myocardial fibrosis and scar resulting after adjustment for demographics and CVD risk fac- from MI may explain some of the higher HF risks in tors in a recent analysis.41 HIV. This may be particularly true if the myocardium Whether specific antiretrovirals predispose to or pro- of PLWH is highly vulnerable to ischemia191 and MI, tect from HF remains controversial. The mitochondrial resulting in larger areas of scar and dysfunction af- toxicity of some older-generation NRTIs (zalcitabine, di- ter MI for PLWH, as a study of PLWH and uninfected danosine, stavudine, and zidovudine) led to concerns people who underwent coronary angiography and related to cardiomyopathy development,124,195 whereas
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Figure 4. Pragmatic approach to atherosclerotic cardiovascular disease (ASCVD) risk assessment and prevention in treated HIV infection. This figure applies to people with treated HIV. For people with uncontrolled HIV, the first priority is appropriate HIV therapy to achieve viral suppression per the HIV provider. Thresholds based on findings of elevated CVD risk at current or nadir CD4 count <200, <350, and <500 cells/mm3 in Silverberg et al,25 Lichtenstein et al,26 and Triant et al.27 Hazard ratios and incidence rate ratios of 1.4 to 2.1 for myocardial infarction (MI) for people living with HIV (PLWH) vs uninfected people demonstrated in Freiberg et al,5 Triant et al,24 and Silverberg et al.25 Hazard ratio of stroke for PLWH vs uninfected people was 1.40 in Chow et al.8 ABI indicates ankle-brachial index; ACC/AHA, American College of Cardiology/American Heart Association; apoB, apolipoprotein B; ART, antiretroviral therapy; CAC, coronary artery calcium; CAD, coronary artery disease; CK, creatine kinase; CVD, cardiovascular disease; D:A:D, Data Collection on Adverse Events of Anti-HIV Drugs; hs- CRP, high sensitivity C-reactive protein; LFT, liver function test; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein A; and PCSK9, proprotein convertase subtilisin-kexin type 9.
concerns are more mixed for contemporary NRTIs: Aba- associations of other specific antiretrovirals with HF. In cavir has inconsistently been associated with elevated any case, the cardiovascular and general health ben- MI (but not necessarily HF) risk,196,197 whereas tenofovir efits of taking ART clearly outweigh the risks according disoproxil fumarate was associated with a lower HF risk to large, seminal studies of ART strategy favoring early among veterans with HIV.198 Data are lacking on the and continuous ART.83,116
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CVD RISK ASSESSMENT IN HIV* CVD risk assessment in HIV is challenging given the relatively recent evolution of HIV as a chronic disease and the resulting dearth of long-term data on CVD incidence in the modern ART era.199 In general, the purpose of predicting disease risk is to inform the risk-
AND GUIDELINES benefit calculus of different preventive interventions.
CLINICAL STATEMENTS STATEMENTS CLINICAL Theoretically, the higher the person’s risk is for a partic-
ular disease, whether over the next 5 or 10 years or the Figure 5. Cardiovascular risk of HIV compared with traditional risk course of a lifetime, the greater the absolute risk reduc- factors. tion (benefit) from therapy is, and the higher tolerance OR indicates odds ratio; PAR, population-attributable risk; and RR, relative risk. Reprinted from Hsue and Waters.209 Copyright © 2018, American Heart is for some amount of risk from the intervention. The Association, Inc. 2013 and 2018 American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines on CVD D:A:D model among PLWH using HIV cohorts in the risk assessment200 and lipid-lowering therapy201,202 ap- United States (multicenter214–216 and single center217), plied this principle, defining groups of adults in whom Europe,218,219 and Sub-Saharan Africa.220 Although the the benefit of statin therapy generally outweighs the individual conclusions on model performance in these risks resulting from elevated absolute risks for ASCVD: studies varied slightly depending in large part on the ≥21 years of age with clinical ASCVD (known coronary validation cohort used, the CVD risk prediction models artery disease or stroke) and/or significantly elevated performed similarly overall, with apparent underesti- LDL-C (≥190 mg/dl) and 40 to 75 years old with dia- mation of CVD risk among PLWH.214,216,217 Therefore, a betes mellitus and/or ≥7.5% 10-year ASCVD risk ac- clear best risk estimation model for HIV has not been cording to the ACC/AHA ASCVD Risk Calculator.203 The identified. European Society of Cardiology applied a similar cen- The presence and extent of subclinical atherosclero- tral principle in its 2016 guideline on CVD prevention, sis can be used to refine CVD risk, especially in those although with a different risk prediction model.204 Al- considered to be at intermediate risk.19 CAC, measured though differences certainly exist among CVD risk pre- from noncontrast CT scans, is a potent predictor of Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 diction equations, they are broadly similar in that they coronary heart disease events and has been studied ex- predict a person’s risk of CVD on the basis of risk factor tensively in the general population.20 However, assess- levels known to be associated with CVD.205–208 ment of CAC alone may not reflect underlying coronary Traditional ASCVD risk factors such as age, diabetes artery disease among PLWH because they have more mellitus, current smoking, hypertension, and dyslipid- noncalcified plaque than uninfected individuals, and emia are associated with elevated ASCVD risk among this can be detected only with coronary CT angiogra- PLWH just as they are in the general population.5,24,34 phy.161 CT angiography is not recommended for screen- Similar to traditional ASCVD risk factors, HIV infection ing in asymptomatic individuals. The ability of CAC to is associated with elevated ASCVD risk (Figure 5),209 discriminate risk for coronary heart disease events in particularly for PLWH with low current or nadir CD4 PLWH has not been determined; however, those with count (especially <200 cells/mm3)5,25,26,210 or a history CAC (particularly if extensive) can be presumed to be of sustained untreated HIV.5,210 No general population at elevated risk. Carotid IMT is also a predictor of fu- risk assessment models have focused on PLWH. The 221 211 ture MI and stroke in the general population and has D:A:D study used a large, primarily white European 222,223 cohort to derive a CVD risk prediction model among been associated with mortality in HIV. PLWH.212,213 The D:A:D model incorporates traditional In the absence of robust data on the adjunctive ASCVD risk factors in addition to certain HIV-specific value of subclinical imaging and biomarker levels for factors associated with CVD (CD4 count, cumulative ASCVD risk stratification among PLWH, it is reasonable exposure to PIs and NRTIs, and current abacavir use). to consider selected ASCVD risk enhancers identified in the 2018 ACC/AHA cholesterol clinical practice guide- Several studies have evaluated CVD risk estimation 202 models derived from the general population or the lines as likely ASCVD risk enhancers in HIV (Figure 4). These include early family history of MI or stroke (men, age <55 years; women, age <65 years), persistently el- *Note: The sections on CVD risk assessment and prevention in evated LDL-C ≥160 mg/dL (≥4.1 mmol/L), chronic kid- HIV are accompanied by Figure 4, which provides a pragmatic approach to ASCVD risk assessment and prevention in ney disease, preeclampsia or premature menopause, treated HIV infection based on available evidence. The lack subclinical atherosclerosis on imaging (including CAC), of data related to HF risk assessment in HIV and adjudicated and high levels of selected biomarkers associated with HF events in HIV precludes informed discussions of HF risk elevated ASCVD risk independently of traditional risk assessment here. factors (Lp(a) [lipoprotein(a)], hsCRP, and apoB [apoli-
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poprotein B]).202 Unlike the 2018 ACC/AHA guidelines, healthy protein sources (fish/seafood, nuts, low-fat CLINICAL STATEMENTS
we did not include elevated triglycerides as a significant poultry, and low-fat dairy), whole grains, and nontropi- AND GUIDELINES ASCVD risk enhancer in HIV because studies in large HIV cal vegetable oils while limiting intake of sweets, sugar- cohorts demonstrated that triglyceride levels, which are sweetened and artificially sweetened beverages (asso- often labile and sensitive to ART changes in HIV, either ciated with coronary plaque burden in HIV239), and red were not predictive of CVD end points independently meats.202 of other traditional CVD risk factors or were associated with marginally elevated ASCVD risk.224–226 At present, there are insufficient data to recommend routine mea- Pharmaco-Prevention of Coronary Artery surement of subclinical atherosclerosis on imaging or Disease in HIV inflammatory biomarkers because the additive value of Primary prevention to reduce the risk of ASCVD is an these measurements for CVD risk stratification in HIV is important goal for PLWH. Statins significantly reduce unclear. Nevertheless, if already measured, atheroscle- CVD events in patients without HIV with increased in- rosis on imaging and elevated levels of Lp(a), hsCRP, or flammation and low levels of LDL-C.240 As discussed, apoB suggest higher ASCVD risk and may warrant more PLWH often present with normal LDL but increased aggressive strategies for ASCVD prevention (Figure 4). systemic and arterial inflammation72 and persistent im- mune activation despite successful ART.241 Traditional CVD risk factors, particularly smoking, are also more PREVENTION AND TREATMENT OF common and should be targeted in HIV.242 HIV-ASSOCIATED ASCVD AND HF Statin use in HIV is complicated by potential drug interactions, although newer statin and ART therapies Lifestyle Optimization appear to have more benign drug-drug interaction pro- As in the general population,200–202 adherence to a files.243 Potent cytochrome P450 (CYP) inhibitors such healthy lifestyle is an essential first step for primary and as ritonavir and cobicistat interact with specific statins secondary prevention of CVD among PLWH. Smoking with significant CYP metabolism.244 Simvastatin and lo- cessation is of paramount importance given the high vastatin are extensively metabolized by the CYP system prevalence of smoking among PLWH143 and the clear and can have levels increased >500% when coadmin- role of smoking in atherosclerosis and MI.144,145 (An ex- istered with CYP inhibitors; accordingly, they should be Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 tensive library of resources for patients and providers to avoided in HIV.244–246 Pravastatin and pitavastatin are approach smoking cessation can be found online.227,228) least likely to interact with ART because of minimal CYP Limiting alcohol consumption is likewise important giv- metabolism, whereas atorvastatin and rosuvastatin, en the potential disproportionate contribution of alco- the 2 highest-intensity statins, with LDL-C lowering of hol to CVD in HIV.19 Although it is clear that heavy alco- >50% at the highest commonly prescribed doses, have hol consumption has adverse effects on CVD and other modest interactions with ART.244,245 A comprehensive disease end points,229 there is debate about whether guide to HIV medications and drug-drug interactions a “healthy” level of alcohol consumption exists; some may be found online.247 large analyses suggested a cardioprotective effect of In terms of clinical adverse events, observational co- light to moderate alcohol consumption (<100 g/wk horts have shown that most statins (simvastatin and [<7 drinks/wk]),230,231 whereas others found no benefit lovastatin excluded) can be safely prescribed for PLWH and perhaps elevated HF and stroke risks for light to with lipid-lowering effects similar to those for people moderate alcohol consumption.232,233 Regular physical without HIV.248,249 A caveat to this may be people >75 activity is also an essential aspect of lifestyle optimiza- years of age, for whom there are conflicting data on tion in HIV given the associations of physical inactivity net statin benefits in the general population.250–252 As with poor health and adherence in HIV and, conversely, in the general population, vitamin D deficiency also is the improvement in inflammation and cardiometabolic associated with statin intolerance in HIV.253 In a ran- health with increasing physical activity in HIV.226,234,235 domized study among hypercholesterolemic PLWH, (HIV-specific resources for exercise and physical activity pitavastatin lowered LDL more than pravastatin, and can be found online.236,237) A randomized trial of sed- neither was associated with increases in glucose, an entary PLWH at high risk for CVD demonstrated fea- important consideration for PLWH.254 In this study, sibility of a lifestyle-focused behavioral intervention to pitavastatin also lowered soluble CD14, oxidized LDL, reduce sweetened beverage consumption and weight, and Lp-PLA2 (lipoprotein-associated phospholipase 2), although there was no significant effect of the inter- important markers of innate immune function and arte- vention on physical activity levels.238 Absent HIV-specific rial inflammation, but did not significantly lower IL-6 or data on optimal diets to prevent CVD, adherence to hsCRP.255 A randomized controlled trial of rosuvastatin ACC/AHA dietary guidelines is recommended. This di- 10 mg versus placebo among PLWH demonstrated a etary approach emphasizes vegetables, fruits, legumes, reduction in some markers of inflammation, monocyte
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activation markers, and vascular inflammation with ro- ducted between 2003 and 2015 suggests that after suvastatin.256,257 There was a significant increase rela- percutaneous coronary intervention, PLWH have simi- tive to placebo in insulin resistance but no significant lar mortality, cardiac death, recurrent MI, target vessel
difference in fasting glucose, hemoglobin A1c, or the revascularization, target lesion revascularization, ma- incidence of diabetes mellitus.258 However, other stud- jor adverse cardiac events, and stroke (pooled hazard ies have not shown effects on specific inflammatory in- ratios, 1.13–1.47; all P>0.15) compared with uninfect- dexes, including IL-6, hsCRP, and D-dimer.84,85 Efficacy ed control subjects over 1 to 3 years of follow-up. De- AND GUIDELINES data for the primary prevention of ASCVD are not yet spite this and further evidence that drug-eluting stents CLINICAL STATEMENTS STATEMENTS CLINICAL available, and statins may be underused in HIV.215,259,260 (compared with bare metal stents) are associated with To address this knowledge gap, the National Insti- better outcomes among PLWH,278,279 PLWH were less tutes of Health launched REPRIEVE, a randomized, pla- likely to undergo percutaneous coronary interven- cebo-controlled, 7,500-person global trial to test a pri- tion and less likely to receive drug-eluting stents after mary prevention strategy in HIV.261,262 REPRIEVE includes acute MI compared with uninfected control subjects patients at low to moderate risk and assesses whether in a propensity-matched analyses of the US Nation- treatment with pitavastatin will prevent adjudicated wide Inpatient Sample.279 Furthermore, women with major adverse cardiovascular events. REPRIEVE will also HIV appear to be less likely than men with HIV to re- assess the degree to which changes in lipids, immune ceive invasive cardiac procedures.280 In the nonacute activation, and inflammation contribute to this effect. setting, however, 1 single-center study showed that Furthermore, little is known about the differential ef- PLWH were more likely to receive percutaneous coro- fects of statins in women with HIV, but immune activa- nary intervention after an abnormal stress test.191 As tion is higher among women.159 This knowledge gap is with other aspects of CVD among PLWH, inflamma- being investigated in REPRIEVE, which has enrolled a tion and immune activation appear to be important high percentage of female PLWH. drivers of restenosis risk after stent placement.270,281 In addition to statin therapy, other strategies to po- For those with more advanced disease or complex tentially reduce CVD risk in HIV include antithrombotic anatomy, coronary artery bypass graft surgery appears agents, which may be underused in HIV263 but have not to be safe and effective for PLWH without advanced yet been assessed in prospective studies powered to immunosuppression, with similar inpatient mortal-
Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 evaluate CVD events. Given the prothrombotic milieu ity and only modestly higher rates of postoperative common in HIV,61,264–266 inconsistent findings related to blood transfusions (adjusted odds ratio, 1.19 [95% CI, aspirin effects on inflammation and endothelial dys- 1.01–1.40]).282,283 However, rates of longer-term ma- function in HIV,86,267 and the tradeoff seen between jor adverse cardiac events after coronary artery bypass reduced vascular events and increased bleeding with graft surgery may be higher for PLWH compared with aspirin for primary ASCVD prevention in non-HIV popu- uninfected individuals.283 lations,268 further studies are needed to elucidate the Although aggressive secondary ASCVD preven- role of antithrombotic therapy for ASCVD prevention tion measures are indicated for PLWH, uptake has not in HIV. Diabetes mellitus and hypertension should be been consistent. Compared with uninfected individu- managed as recommended for the general population als, PLWH are less frequently prescribed high-intensity because there are insufficient data to recommend a di- statin after acute coronary syndrome (15% versus vergent approach in HIV. 45%), and LDL reduction 6 months after the acute A practical expert consensus approach to ASCVD coronary syndrome event is lower.284 Similarly, 57% risk assessment and primary prevention in HIV that is of PLWH with prior CVD events did not meet guide- based on available (albeit incomplete) evidence is pro- line-recommended blood pressure targets in a Dutch vided in Figure 4. study.285 With regard to aspirin use, a similar differ- ence in secondary prevention exists, with only 52% of PLWH with coronary disease on aspirin compared Acute Coronary Syndromes and with 65% of uninfected people in a large urban health Secondary Prevention of Coronary Artery system.263 Disease PLWH who experience an acute coronary syndrome Nonstatin Strategies to Prevent ASCVD such as ST-segment–elevation and non–ST-segment– and to Reduce Inflammation in HIV: elevation MI tend to have lower overall coronary plaque burden,269 more single-vessel disease,270 lower Investigational Approaches TIMI (Thrombolysis in Myocardial Infarction) risk,270 and Both initiation of ART60 and early initiation of ART286 a higher likelihood of proximal lesions than uninfected lower inflammation in HIV, but levels remain high com- individual.271 A meta-analysis272 of 6 studies273–278 con- pared with levels in uninfected people. Similarly, switch-
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ing ART regimens (namely a PI-based to an integrase but also increased the rate of fatal infections in CAN- CLINICAL STATEMENTS
inhibitor–based strategy) or intensifying ART does not TOS (Canakinumab Anti-Inflammatory Thrombosis AND GUIDELINES appear to significantly reduce inflammatory mark- Outcomes Study).90 Treatment with canakinumab was ers.287–290 These findings suggest that alternative and also associated with a significant reduction in incident adjunctive approaches may be needed to reduce excess lung cancer and lung cancer mortality, although this ASCVD risk in HIV. was not the primary study end point.91 Individuals who In recent years, several studies of lipid-lowering achieved an on-treatment hsCRP <2 mg/L had rela- therapies added to a background of statin therapy tive reductions in both cardiovascular mortality and have demonstrated that aggressive LDL-C lowering in all-cause mortality by 31% compared with placebo92; populations at high ASCVD risk reduces cardiovascular a similar finding was demonstrated for individuals events.291,292 The benefit of aggressive LDL-C lowering with on-treatment IL-6 <1.65 ng/L.298 Conversely, in is demonstrated by data from 14 large statin studies the CIRT trial (Cardiovascular Inflammation Reduction in the non-HIV population (Cholesterol Treatment Trial- Trial) of uninfected individuals with stable atheroscle- ists’ Collaborators) in which each 38.6-mg/dL reduc- rosis, low-dose methotrexate did not reduce inflam- tion in LDL-C translated to a reduction in cardiovascular matory biomarkers or CVD events.299 In this study, events by 22%.293 PCSK9 (proprotein convertase sub- methotrexate was associated with elevations in liver tilsin-kexin type 9) binds and degrades LDL receptors, transaminases and reductions in leukocyte counts. In leading to an increase in LDL-C.294 PCSK9 inhibitors are light of the positive results from CANTOS (with the monoclonal antibodies with minimal significant drug- notable exception of increased fatal infections) and drug interactions identified thus far that reduce LDL-C the null findings from CIRT, further study is needed to by ≈60% even in the setting of high-intensity statin define the role of targeted therapies to reduce inflam- therapy.292 Two PCSK9 inhibitors are approved by the mation and CVD risk in HIV. US Food and Drug Administration for individuals with heterozygous familial cholesterolemia or clinical AS- CVD on maximally tolerated statins who require addi- Stroke Prevention and Therapy in HIV tional LDL-C lowering. Among uninfected people with Although the risk for ischemic stroke is elevated in HIV,8 ASCVD, PCSK9 inhibitor therapy in addition to statin data on pharmacotherapy for stroke prevention in HIV therapy reduced clinical events by 15% (P<0.001).292 A are sparse. Whereas systemic atherosclerosis is a likely Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 longer study demonstrated that PCSK9 inhibitor thera- driver of the elevated stroke risk in HIV, atrial fibrillation py reduced rates of major adverse cardiovascular events (which may be more common overall in HIV but not af- significantly overall and reduced mortality among indi- ter adjustment for common CVD risk factors)41 accounts viduals with an LDL-C ≥100 mg/dL.295 PCSK9 levels are for 30% of ischemic stroke among PLWH.169 Using risk
higher in PLWH than in uninfected person, particularly stratification tools, for example, the CHA2DS2-VASc and in the setting of hepatitis C virus coinfection, and are HAS-BLED scores, to estimate cardioembolic stroke and increased in parallel with inflammatory markers such hemorrhagic complications of antithrombotic therapy, as IL-6.296 This relationship may be more pronounced respectively, is an important step to rationalize primary among individuals who are ART naïve.297 A clinical trial and secondary intervention in general and perhaps in investigating the impact of PCSK9 inhibitor therapy on HIV.300 However, the reliability of these scores in PLWH is lipids, inflammatory markers, and subclinical ASCVD unclear,300 as are the safety of anticoagulants (particu- (including noncalcified plaque and arterial inflamma- larly direct-acting oral anticoagulants) and their interac- tion) in HIV is currently being conducted (EPIC-HIV tions with ART.168,301 study [Effect of PCSK9 Inhibition on Cardiovascular There are no trials on the safety and efficacy of Risk in Treated HIV Infection]; URL: ClinicalTrials.gov. thrombolysis in HIV infection, but retrospective studies Unique identifier: NCT 03207945). Future studies are have shown that the risk of death with thrombolysis was needed to evaluate the impact of PCSK9 inhibition on similar for PLWH and uninfected individuals.302,303 Endo- clinical events in HIV. vascular treatment is now routine in acute stroke treat- As discussed, chronic inflammation and immune ment304; 1 case series, with limited safety data, showed activation remain elevated in effectively treated HIV successful endovascular treatment in patients with HIV- infection60 and are strongly predictive of non-AIDS associated vasculopathy.305 HIV-associated vasculitis events, including CVD and mortality.67,68 In particular, may manifest as acute stroke, driven by inflammation IL-6 and D-dimer are strongly associated with mortal- alone or secondary infection. This may occur soon after ity in HIV.64 In the non-HIV population with known the patient starts ART, suggesting an immune recon- CVD and hsCRP ≥2 mg/L, treatment with a mono- stitution inflammatory syndrome.170 Optimal workup, clonal antibody targeting IL-1β (canakinumab) sig- including cerebral angiogram and lumbar puncture, if nificantly reduced IL-6 and hsCRP and led to a sig- safe, is essential in diagnosing this potentially treatable nificantly lower rate of recurrent cardiovascular events pathogenesis.171 High-dose corticosteroids may be nec-
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essary in patients with immune reconstitution inflam- There are well-documented disparities in care for matory syndrome with impending brain herniation and CVD among PLWH. PLWH have fewer clinic visits that helpful in less severe cases with symptomatic central meet guideline-directed medical therapy for aspirin nervous system inflammation.306 therapy (5.1% versus 13.8%) and use of statins (23.6% versus 35.8%).21 Data from a large cohort of PLWH in Europe demonstrated that women are less likely to re- HF Diagnosis and Treatment ceive lipid-lowering therapy, antihypertensive medica- AND GUIDELINES The uncertainty about the mechanisms and course of tions, angiotensin-converting enzyme inhibitors, and CLINICAL STATEMENTS STATEMENTS CLINICAL HF in HIV precludes evidence-based recommendations invasive cardiovascular procedures after MI.311 Data on HIV-specific HF diagnosis and treatment. There are from the Veteran’s Health Administration Corporate insufficient data to suggest approaches to HF workup Data Warehouse also demonstrate that blood pressure, and therapy differing from those used in the general diabetes mellitus, and lipid management are worse in population. However, given the elevated risks for HF in black compared with white PLWH.312 Black and His- HIV, it would be reasonable for clinicians engaged in panic PLWH have among the highest estimated 10-year the care of PLWH to have a high index of suspicion for risk of ASCVD compared with other racial and ethnic HF in the setting of possible HF symptoms, along with groups.214,313 Substance-related disorders also impair a low threshold to pursue noninvasive diagnostic test- CVD care in PLWH; they are associated with less ap- ing (such as echocardiography) in the setting of such propriate statin use (23% versus 40%) compared with symptoms or cumulative exposures to high-risk fea- those without substance-related disorders.314 Such dis- tures (eg, high cumulative viremia, low CD4 count, or parities in CVD prevention for PLWH portend greater substance abuse). Furthermore, given the importance risk for MI.315 Furthermore, major depressive disorder of left ventricular EF as a predictor of sudden cardiac is particularly common in HIV and associated with el- death for PLWH307 (as in the general population), it is evated risk for HF in HIV.36 reasonable to follow general population indications for Geographic factors also affect CVD prevention and implantable cardioverter-defibrillator therapy in PLWH. management. MI, stroke, and stroke mortality rates For PLWH with end-stage HF requiring advanced thera- are up to 4 times higher in the South compared with 316–318 pies, HIV should not be considered a contraindication other regions in the United States. HIV prevalence is highest in the South, with significant racial disparities Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 to transplantation or left ventricular assist device im- 319 plantation given the longer life expectancy of PLWH, in incidence and prevalence. Black men and women which is approaching that of uninfected people.308 have lower rates of HIV viral suppression, which pre- disposes to more inflammation and CVD. On a global landscape, 67% of all PLWH reside in Sub-Saharan DISPARITIES IN CARE AND PLWH AS A Africa. A large systematic review and meta-analysis of VULNERABLE POPULATION longitudinal studies of CVD in HIV infection examined CVD rates among PLWH worldwide.4 Between 1990 PLWH represent a vulnerable and often stigmatized and 2015, the global population-attributable fraction population that faces structural and economic barriers of CVD caused by HIV tripled from 0.36% to 0.92%. to optimal healthcare services.309 Understanding and There was marked regional variation, with most car- addressing CVD in PLWH necessitates recognizing the diovascular disability-adjusted life-years lost in the Sub- systematic barriers that perpetuate disparities in care Saharan Africa (0.87 million) and Asia-Pacific (0.39 mil- delivery. (A comprehensive review of HIV-associated lion) regions. CVD in resource-limited settings is beyond the scope of this statement; however, given the clear importance of this topic, we have included a brief discussion here.) Addressing Disparities: Opportunities for Many factors exacerbate vulnerability for PLWH, Positive Impact including education level, residential location, health- Given the physiological, socioeconomic, and geograph- care literacy, disenfranchisement from the healthcare ic factors that make PLWH particularly vulnerable to the system, cognitive impairment, injection drug use, in- onset and progression of CVD, there is considerable ternalized and anticipated stigma, gait and mobility room for improvement in CVD prevention and treat- impairment, frailty, depression, and social isolation. ment. The investment in HIV care and research over the These factors can be intensified by disparities in care years has resulted in a growing infrastructure and strat- according to individual factors such as age, race, eth- egies that can be leveraged for optimal CVD prevention nicity, and sex, as well as factors associated with high and management. The HIV treatment cascade and the HIV transmission rates such as homosexual contact be- global 90-90-90 initiatives aim to maximize diagnosis, tween men, heterosexual contact among black wom- treatment, and viral suppression.320 Expanding the HIV en, and injection drug use.310 treatment cascade for the prevention of non-AIDS co-
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morbidities is a necessary extension of the treatment crease risks for MI, stroke, and HF. Several studies have CLINICAL STATEMENTS
cascade paradigm.321 Empowered PLWH are also driv- analyzed the pathophysiology of atherosclerosis in HIV, AND GUIDELINES ing the conversation about CVD prevention and man- but relatively few have been devoted to understand- agement (see the Data Supplement: HIV, Aging, and ing thrombosis and HF. Therefore, further studies of the Patient’s Perspective) through the use of publicly the pathophysiology of thrombosis and HF in HIV are available resources such as the National AIDS Treatment sorely needed. Similarly important is the lack of large- Advocacy Project.322 scale clinical trials on CVD prevention and treatment in Targeted attention and investment are needed. The HIV; these trials are necessary for informed decision- quality of our care for HIV is further limited by short- making and effective CVD prevention and treatment in comings in the US healthcare reimbursement system. the aging HIV population. In the meantime, a reason- Healthcare providers are often unable to spend the able approach may be to consider PLWH at particularly time required to understand the problems facing the elevated CVD risk and therefore more likely to benefit aging HIV population. PLWH who also have CVD of- from CVD-preventive therapy if risk-enhancing fac- ten need longer visit times,323 care coordination, and tors that are related to HIV (eg, low current or nadir multidisciplinary team engagement. There are many CD4 count or a history of prolonged viremia) or are opportunities for implementation research aimed at more general (eg, family history of premature ASCVD, leveraging the HIV care infrastructure to deliver inte- chronic kidney disease, or atherosclerosis on imaging) grated cardiovascular preventive and therapeutic care are present. Future studies should also address gaps in for PLWH.324 Such structures could include improving implementation to ensure that PLWH who are at risk health insurance access to specialists, strengthening for CVD or have existing CVD are identified and pro- specialist referral pathways, nurse management, clini- vided appropriate CVD care. If these steps are taken, cal pharmacist engagement,325 team-based approach- perhaps we can reverse the trend of the growing bur- es,326 electronic medical record–based approaches to den of CVD in HIV. targeting high-risk patients, colocated clinics, and oth- er approaches that consider the specific vulnerabilities ARTICLE INFORMATION in this population. The American Heart Association makes every effort to avoid any actual or po- Models of integration of primary care and HIV ser- tential conflicts of interest that may arise as a result of an outside relationship or
Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 vices have been demonstrated to be feasible and effec- a personal, professional, or business interest of a member of the writing panel. 327 Specifically, all members of the writing group are required to complete and tive, but little information is available on cost or ef- submit a Disclosure Questionnaire showing all such relationships that might be fectiveness of specific approaches in the United States. perceived as real or potential conflicts of interest. A research agenda has been suggested for Sub-Saha- This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on February 5, 2019, and the Ameri- ran Africa that prioritizes developing evidence-based can Heart Association Executive Committee on February 19, 2019. A copy of service delivery models, generating data through infor- the document is available at https://professional.heart.org/statements by using matics platforms and research, and advancing research- either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@ informed policy, among other cross-cutting health sys- wolterskluwer.com. tem issues. The impact of interventions to reduce the The online-only Data Supplement is available with this article at https:// burden of CVD in PLWH in the United States likewise www.ahajournals.org/doi/suppl/10.1161/CIR.0000000000000695. The American Heart Association requests that this document be cited as needs to be evaluated and optimized. This will require follows: Feinstein MJ, Hsue PY, Benjamin LA, Bloomfield GS, Currier JS, Freiberg continued funding support from the National Institutes MS, Grinspoon SK, Levin J, Longenecker CT, Post WS; on behalf of the Ameri- of Health and public-private partnerships, including can Heart Association Prevention Science Committee of the Council on Epide- miology and Prevention and Council on Cardiovascular and Stroke Nursing; support from industry to study the effects of emerging Council on Clinical Cardiology; and Stroke Council. Characteristics, prevention, therapies. and management of cardiovascular disease in people living with HIV: a scientific statement from the American Heart Association. Circulation. 2019;139:e00– e00. doi: 10.1161/CIR.0000000000000695. The expert peer review of AHA-commissioned documents (eg, scientific CONCLUSIONS AND FUTURE statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines DIRECTIONS development, visit https://professional.heart.org/statements. Select the “Guide- lines & Statements” drop-down menu, then click “Publication Development.” Although much progress has been made over the past Permissions: Multiple copies, modification, alteration, enhancement, and/ decade in understanding HIV-associated CVD, consid- or distribution of this document are not permitted without the express permis- erable gaps exist, and much work remains to be done sion of the American Heart Association. Instructions for obtaining permission are located at https://www.heart.org/permissions. A link to the “Copyright Per- in the future. Even with effective HIV viral suppression, missions Request Form” appears in the second paragraph (https://www.heart. inflammation and immune dysregulation appear to in- org/en/about-us/statements-and-policies/copyright-request-form).
Circulation. 2019;139:00–00. DOI: 10.1161/CIR.0000000000000695 TBD TBD, 2019 e15 Feinstein et al Cardiovascular Disease in People With HIV
Disclosures
Writing Group Disclosures
Writing Other Speakers’ Group Research Bureau/ Expert Ownership Consultant/ Member Employment Research Grant Support Honoraria Witness Interest Advisory Board Other Matthew J. Northwestern AHA (research support)†; None None None None None None
AND GUIDELINES Feinstein University NIH (research support)†
CLINICAL STATEMENTS STATEMENTS CLINICAL Priscilla Y. Hsue San Francisco NIH (grant support)†; None None None None Gilead*; Merck* None General Hospital Regeneron/Sanofi (study drug and placebo provided for trial)*; Novartis (study drug and placebo provided for trial)* Laura A. University of None None None None None None None Benjamin Liverpool Institute of Infection and Global Health Gerald S. Duke Clinical NIH (research grant None None None None None None Bloomfield Research Institute, R01MD013493)* Duke Global Health Institute and Duke University Medical Center Judith S. Center for AIDS NIH grant (steering None None None None None None Currier Research and committee of REPRIEVE Education trial)*; Theratechnologies (PI of clinical trial at UCLA, ended June 2018)* Matthew S. Vanderbilt University NIH (grants studying HIV None None None None None None Freiberg and CVD)†
Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 Steven K. Massachusetts Gilead†; KOWA†; None None None None Theratechnologies* None Grinspoon General Hospital Navidea*; Theratechnologies* (all to institution); NIH (P30 Center Grant)† Jules Levin National AIDS None None None None None None None Treatment Advocacy Project Chris T. Case Western Gilead Sciences (ISR)† None None None None None None Longenecker Reserve University School of Medicine Wendy S. Post Johns Hopkins NIH (to Hopkins)† None None None None None None University, Johns Hopkins Hospital
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. *Modest. †Significant.
e16 TBD TBD, 2019 Circulation. 2019;139:00–00. DOI: 10.1161/CIR.0000000000000695 Feinstein et al Cardiovascular Disease in People With HIV
Reviewer Disclosures CLINICAL STATEMENTS
Other Speakers’ Consultant/ AND GUIDELINES Research Bureau/ Expert Ownership Advisory Reviewer Employment Research Grant Support Honoraria Witness Interest Board Other Edgar University of Alabama at None None None None None Merck*; ViiV* None Overton Birmingham Virginia A. Massachusetts General NIH (co-PI of R01 on None None None None None None Triant Hospital–Harvard Medical cardiovascular risk prediction School in HIV)†
Allison R. Case Western Reserve Gilead Sciences (My university None Association of None None None None Webel University received a research grant for Nurses in AIDS our work from Gilead)† Care*
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. *Modest. †Significant.
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